Cognitive decline is a common sequela of mammalian aging, from rodents to humans. As it often results in the inability to live independently, slowing or preventing the loss of cognition with age would significantly increase the quality of life for older adults. While the etiology of age-related cognitive impairment is unknown, there is increasing evidence that age-related changes in neurotransmitters may play an important role. Neurotransmitters produced from proopiomelanocortin (POMC) are of particular interest because they modulate cognition, metabolic rate and other age-related phenotypes, and their levels are known to decrease with age. Furthermore, when administered systemically, or into the brain, they improve memory, attention, and cognition and delay the decline in cognition in mouse models of Alzheimer?s disease. However, which POMC- producing neurons are responsible for the age-related decline in brain POMC, the mechanism by which this occurs, and its contribution to age-dependent cognitive decline are not known. Our studies will yield insight into mechanisms responsible for age-related changes in POMCHipp neurons and reveal whether interventions that delay aging act, in part, by modulating these neurons. Filling these gaps in knowledge is essential f or development of interventions to reverse cognitive aging. The proposed work is enabled by a novel combination of technology including retrograde labeling of POMCHipp neurons and mouse genetic models that together allow us to specifically target these neurons. This will allow us to analyze age-dependent changes in the number and projection density (Aim 1) and gene expression (Aim 2) of POMCHipp neurons that may provide insight into the decline in cognition with age. We will further determine whether these changes can be reversed by treatment with rapamycin, a drug that increases lifespan in mice while ameliorating age-related declines in cognition, as well the age-related dysfuncton of Arc POMCPVN neurons. Finally, in Aim 3 we will specifically activate or inhibit the function of Arc POMCHipp neurons and measure the impact on cognition. Our approach is highly innovative and will define the role POMCHipp neurons in the mechanisms responsible for cognitive decline with age, and provide a framework for studies to develop interventions to reduce age-related cognitive decline. This JPI project will provide the preliminary data, mentorship, and resources for the development of a competitive, independent research grant proposal in the field of geroscience.